Influenza A virus infections and their associated pulmonary complications cause excess mortality and substantial morbidity on a nationwide scale. No specific therapy of proven value exists for primary viral pneumonia or the viral component of the more frequent mixed viral-bacterial pneumonias secondary to influenza A virus infection. In uncomplicated influenza early treatment with amantadine HCl or rimantadine HCl is associated with a moderate therapeutic effect, but the use of higher doses is limited by dose-related toxicity. Previous work has suggested treatment alternatives to single drug therapy. In vitro studies by the principal investigator have shown that combinations of rimantadine HCl and ribavirin result in an enhanced antiviral effect relative to single drugs. Other workers report a failure of the interferon response in fatal cases of human influenza viral pneumonia. Methods to augment (passive antibody) or to alter (anti-inflammatory agents) host defense mechanisms appear to ameliorate the course of influenza in animal models. The goal of the proposed study is to assess these therapeutic approaches in a murine model of pneumonic disease. The therapeutic effects of combinations of antiviral drugs, of exogenous interferon or antibody, alone and in combination with drugs, and of combined corticosteroid and antiviral drug treatment will be studied. Treatments will be initiated at 48 hours after intranasal inoculation, by which time lung virus titers are peaking. Parameters of response will include survival, lung and animal weights, lung consolidation, and lung virus titers. The problem of drug resistant virus will be studied by determining the ease of selecting for resistance in vivo and by assessing the activity of antivirals in mouse protection experiments involving resistant virus.